09: Physiology and Integrative Systems Cellular Mechanobiology: Biophysics and Therapeutics Sanjay Kumar, MD, PhD University of California, Berkeley One of the most important lessons from cellular physiology in the past decade is that living cells sense, process, and physiologically respond to specific physical stimuli in their environment, including the geometry, dimensionality, and rigidity of the extracellular matrix (ECM). This has spawned an intense effort to understand how mechanical cues manifest themselves in the context of problems ranging from stem cell engineering to tumor growth to scar formation, which has collectively led to the genesis of a completely new field: Mechanobiology. Yet, despite this recent flurry of activity, the field of mechanobiology continues to suffer from two limitations which threaten to restrict its long-term progress: mechanistic disagreements about how cells sense and process mechanical cues, and uncertainty about whether mechanobiological relationships observed in vitro also operate in a more clinically relevant setting. Here I propose to advance the field of mechanobiology by addressing both of these issues, organizing my research around three questions: (1) How are intracellular and extracellular mechanical stimuli applied to microscale portions of a living cell chemically and physically communicated to the rest of the cell, and how do these signals physically trigger changes in gene programs?; (2) How does the regulation of specific genes, gene networks, and signaling pathways differentially depend on physical cues from the ECM, such as ECM rigidity, geometry, and dimensionality, and can cells be genetically engineered to alter their responses to these cues?; (3) Can targeting mechanobiological interactions between cells and the ECM influence tissue physiology and pathology in vivo? By directly tackling these questions, we will strengthen the mechanistic foundations of this nascent field and facilitate the creation of cellular engineering and therapeutic strategies which leverage its principles.